Systemic lupus erythematosus in humans and spontaneous mouse models is characterized by autoantibodies to nuclear and cytoplasmic materials that contain RNA, DNA or both, and considerable evidence indicates a direct pathologic role of these autoantibodies. Until recently the mechanisms involved in autoantibody production were to a large extend unclear, however, the emerging knowledge of a diverse array of mammalian sensors for nucleic acids, and the demonstration that these sensors are principal participants in lupus pathogenesis, have now provided a more concise definition of the mechanisms by which this disease is initiated and propagated. Among the innate immune cells implicated in the pathogenesis of lupus is the plasmacytoid dendritic cell (pDC) which constitute a small (<1%), but distinct population of cells that is thought to be activated by nucleic acid-containing immune complex stimulation of endosomal TLRs resulting in the production of disease-promoting type I interferons. Although investigation of the role of pDCs in SLE was previously not possible because of the absence of adequate animal models, recently an ENU mutation in the Slc15a4 gene, called feeble, was discovered that resulted in defective TLR7/9-induced type I interferon production in specifically pDCs. This proposal will utilize this unique model to define the role of pDCs and the production of type I interferons by these cells in animal models of lupus. We will also seek to identify pharmacologic inhibitors of SLC15A4 by high throughput screening. The insights gained from these studies are likely to provide a better understanding of the mechanisms by which innate sensors and cells promote disease, and reveal novel targets for therapeutic intervention.